Targeting MEK/ERK Signaling in MVP

Mitral valve prolapse (MVP) is one of the most common forms of cardiac valve disease, affecting 1 in 40 humans and ~70% of small breed dogs. There are no effective nonsurgical treatments for MVP and therapeutic efforts have been hindered due to an incomplete understanding of its fundamental causes. Recent studies by our group have described the genetic basis for non-syndromic MVP and have provided new insights into molecular processes that underlie the disease. We have used this genetic information to identify druggable targets that can provide a non-surgical option for humans. In particular, we have identified the Mek/Erk pathway as the major disease initiating pathway and prolonged hyperactivation of Mek/Erk drives disease progression and severity. Activation of the Mek/Erk pathway leads to increased proliferation, aberrant differentiation, and production of matrix metallopeptidases (MMPs). Thus, we hypothesize that pharmacological blockade of Mek/Erk activities will sufficiently arrest the disease pathway and maintain the valves in a sub-clinical condition. This hypothesis will be tested by screening novel mitogen-activated protein kinase kinase (MEK1) inhibitors in vitro and in vivo. Results from this study may serve as a stepping stone towards developing the first non-surgical treatment for canine and human patients with MVP.